Myelinummantelung von Nervenfasern/Photo: Charite
Combination therapy could potentially slow down the deterioration of the brain
Berlin, 17 March 2025
The brain’s immune system contributes to the worsening of Alzheimer’s via the inflammatory messenger IL-12. Yet the brain’s immune cells, the microglia, are actually good guardians. They remove intruders such as microbes and clean up cellular waste – including the typical plaques that develop in Alzheimer’s disease. However, in the ageing brain, microglia are found in a wide variety of states. While some continue to function well, others gradually lose their protective effect and begin to produce small amounts of inflammatory messengers on a permanent basis. Researchers from Charité – Universitätsmedizin Berlin and the Max Delbrück Centre describe the exact mechanism in the journal Nature Aging*.
In meticulous analyses, the teams led by Professor Frank Heppner, Director of the Institute of Neuropathology at Charité, and Professor Nikolaus Rajewsky, Director of the Berlin Institute for Medical Systems Biology at the Max Delbrück Center (MDC-BIMSB), together with other partners, have now been able to uncover how the inflammatory messenger IL-12 fuels the development and progression of dementia. Their findings could pave the way for a combination therapy and possibly slow down the deterioration of the brain.
‘For decades, Alzheimer’s research focussed almost exclusively on the characteristic deposits of amyloid beta and tau. Inflammation was considered a side effect,’ says Frank Heppner. ‘The fact that inflammatory processes can be at the beginning of the chain is only gradually coming into focus.’ His laboratory had already reported in 2012 in the journal Nature Medicine that blocking the messenger substances IL-12 and IL-23 can significantly reduce brain changes typical of Alzheimer’s in mice. ‘But we couldn’t unravel the mechanism – we didn’t get any further with standard techniques,’ says Frank Heppner. He hoped that single cell analyses could provide decisive clues and turned to Nikolaus Rajewsky.
Stuck and tangled brain cells
In the course of its life, a cell repeatedly accesses instructions contained in its genetic material. It reads it like a book and learns how it should react to external influences. Researchers can use single cell analyses to observe this process. They can reconstruct which genes have been read and translated into proteins for thousands of cells simultaneously. The result is huge amounts of data that can be analysed with the help of artificial intelligence and machine learning. The catch: for single-cell sequencing, the cells in a tissue sample must first be cleanly separated from each other without damaging or unintentionally manipulating them. ‘In the ageing brains of mice – especially with Alzheimer’s plaques – the cells are so stuck together and tangled that this is virtually impossible,’ says Rajewsky.
His team spent several years perfecting a protocol that avoids this hurdle: instead of whole cells, the researchers removed the cell nuclei from the brain tissue and analysed which RNA was currently present there. By comparing this with published data such as the Allen Brain Atlas, they were able to determine when the protocol provided a representative image of all cell populations. Ultimately, they sequenced the RNA from more than 80,000 cell nuclei and developed specific workflows for analysing the mountains of data. They also reconstructed the communication between the cells. ‘The two teams sat together again and again and discussed what this highly complex data meant,’ says Rajewsky. ‘This painstaking optimisation at the beginning was worth it – the correlations would otherwise not have been measurable.’
How IL-12 Damages the Alzheimer’s Brain
The inflammatory messenger IL-12, which doctors have previously known primarily from autoimmune diseases such as Crohn’s disease or rheumatoid arthritis, plays a central role in the development of Alzheimer’s. It damages two important cell types in the brain: first, the mature oligodendrocytes, which normally produce the fatty insulating layer of nerve fibers, myelin. This insulating layer is crucial for rapid signal transmission in the brain. Second, the messenger binds to certain nerve cells, the interneurons, and causes them to die. These specific nerve cells are particularly important for cognition and memory. A vicious circle begins: The more microglia produce IL-12, the more cells are damaged. And the still-functional microglia are distracted from having to clear away additional cellular waste instead of breaking down Alzheimer’s plaques.
The researchers tested the mechanism in several steps in mice and human tissue. When Frank Heppner’s team blocked the messenger substance in cell cultures and in a mouse model, they were able to contain the disease-related changes. Electron microscopy images at the Max Planck Institute for Multidisciplinary Sciences in Göttingen also demonstrated how myelin structure and nerve fiber density changed when the IL-12 signaling pathway was present or absent in mice.
Mass spectrometric analyses at the University of Zurich confirmed the altered composition of the fatty insulating layer. When Frank Heppner’s team examined autopsy tissue from Alzheimer’s patients, the connection was confirmed again. The more advanced the disease was, the more IL-12 they found. Cell cultures containing human oligodendrocytes also reacted extremely sensitively to IL-12.
Approach for combination therapy
“We now have a very detailed picture of the mechanism, and single-cell technologies were an essential catalyst for this. The only remaining question is which cell type is affected first – the oligodendrocytes, the interneurons, or both,” says Frank Heppner, who is also a scientist at the German Center for Neurodegenerative Diseases (DZNE). Particularly promising: There are already approved drugs on the market that block IL-12. The team now hopes that clinical colleagues will take up the data and start a clinical trial. “If the drugs prove effective, that would be a new arrow in the quiver. Alzheimer’s does not have a single cause. One axis of the disease is controlled by the immune system, at least in some patients. If we want to slow the decline, we need combination therapy,” says Heppner. This can start early, because IL-12 can be detected as a biomarker in the blood or cerebrospinal fluid.
*Schneeberger S et al. Interleukin-12 signaling drives Alzheimer’s disease pathology through disrupting neuronal and oligodendrocyte homeostasis. Nature Aging Mar 13. doi: 10.1038/s43587-025-00816-2